Ion channels are macromolecular pores within cell membranes that control the transport of ions through the lipid bilayer. They open and close in response to changes in a ligand concentration or membrane potential. They maintain ion balance in the cell, control ion-sensitive processes and are responsible for the electrical signals in excitable tissues. There are many disease states that either are caused directly by interference in ion channel function, e.g. C1 transport in cystic fibrosis, or affect ion channel function and/or distribution secondarily, e.g. Na+ channel distribution in multiple sclerosis. This proposal outlines molecular and genetic studies of sodium ion channels that will contribute to the understanding of protein structure/function relationships that can provide the basis for developing reasoned therapeutic strategies. Using the fruit fly DROSOPHILA as a model system for studying voltage- dependent channels offers unique opportunities for describing the function and regulation of these channels. In the fly, powerful techniques exist for analyzing the genomic structure and organization of gene families and manipulating and returning channel genes to the organism in defined genetic backgrounds. Combined with behavioral analysis and sophisticated electrophysiological analysis a detailed description of protein function can be correlated with structural features of the protein. Two putative sodium channel genes have been identified in the fly with strong sequence similarity to the vertebrate genes. Mutants in one of these, the para gene, affect neuronal embryonic sodium currents and their phenotypes suggest that para may be the primary gene coding for sodium channels in these neurons. As yet, the other sequence has not been characterized genetically or physiologically. The aim of this research is to characterize the expression of these genes and develop and genetic and molecular tools that will permit a functional analysis of the gene products.